Characterization of visual cognition in pre-manifest, manifest and reduced penetrance Huntington's disease

Abstract

Cognitive and visual impairment are common in Huntington's Disease (HD) and may precede motor diagnosis. We investigate the early presence of visual cognitive deficits in 181 participants, including HD carriers (40 pre-manifest, 30 early manifest, 27 manifest, and 6 reduced penetrance) and 78 healthy controls (HC). Significant differences in visual memory were observed between reduced penetrance and pre-manifest groups (p = .003), with pre-manifest showing worse performance. Age, education, CAG repeats, motor status, executive function, and verbal fluency, accounted for up to 72.8% of the variance in general and visual cognitive functions, with motor status having the strongest impact on visual domains in HD carriers. In pre-manifest HD, visual cognitive domains were primarily influenced by executive function, verbal fluency, age, and CAG repeats, while in early and manifest stages motor status and verbal fluency becomes more influential. ROC analyses showed that especially visuospatial abilities, visual memory, and visual attention (AUC = 0.927, 0.878, 0.874, respectively) effectively differentiated HC and pre-manifest from early and manifest HD. Early assessment of visual cognitive domains, particularly visual memory, could be an early marker of cognitive decline in HD. Our findings highlight the different profiles of impairment in visual cognition across HD carriers.

Keywords: Cognition; Huntington disease; Pre-manifest; Reduced penetrance; Visual cognition.

Fig. 1

Confirmatory factor analysis of cognitive domains. Note: Visual attention [TMT (Trail Making Test) part A, Stroop Word, Stroop Color, Stroop Word-Color]; Visual processing speed/visual perception [Salthouse Perceptual Comparison Test (SPCT), Symbol Digit Modalities Test (SDMT)]; Visuospatial abilities: [Grooved Pegboard test (GPT), Visual perception with Visual Object and Space Perception Battery (VOSP cubes and dot-counting), Taylor Complex Figure (TFC copy), Benton Judgment of Line Orientation (BJLO)]; Visual Memory: [Brief Visuospatial Memory Test-revised (BVMT-R total score and delayed recall), TFC memory]; Executive Functions: [Modified Wisconsin Card Sorting Test (M-WCST total categories, perseverative errors and total errors), TMT Part B]; Verbal fluency: letters F, A, S, and P.

Fig. 2

Cognitive differences between groups. *p < .05; **p < .01; ***p ≤ .001. Note: HC = Healthy Controls; RP = Reduced Penetrance group. The figure shows the boxplots from the ANCOVA and post hoc analysis performed between groups for each cognitive domain. General Cognition: MoCA total score; Visual attention: [TMT (Trail Making Test) part A, Stroop Word, Stroop Color, Stroop Word-Color]; Visual processing speed/visual perception [Salthouse Perceptual Comparison Test (SPCT), Symbol Digit Modalities Test (SDMT)]; Visuospatial abilities: [Grooved Pegboard test (GPT), Visual perception with Visual Object and Space Perception Battery (VOSP cubes and dot-counting), Taylor Complex Figure (TFC copy), Benton Judgment of Line Orientation (BJLO)]; Visual Memory: [Brief Visuospatial Memory Test-revised (BVMT-R total score and delayed recall), TFC memory]; Executive Functions: [Modified Wisconsin Card Sorting Test (M-WCST total categories, perseverative errors and total errors), TMT Part B]; Verbal fluency: letters F, A, S, and P.

Fig. 3

Predicted effects of age education, clinical data, executive function and verbal fluency in cognition. The figure illustrates the percentage of variance explained by age education and clinical data in each model. Note: Motor status was assessed with the Unified Huntington’s Disease Rating Scale (UHDRS): General cognition was assessed with the Montreal Cognitive Assessment (MoCA). Visual attention [TMT (Trail Making Test) part A, Stroop Word, Stroop Color, Stroop Word-Color]; Visual processing speed/visual perception [Salthouse Perceptual Comparison Test (SPCT), Symbol Digit Modalities Test (SDMT)]; Visuospatial abilities: [Grooved Pegboard test (GPT), Visual perception with Visual Object and Space Perception Battery (VOSP cubes and dot-counting), Taylor Complex Figure (TFC copy), Benton Judgment of Line Orientation (BJLO)]; Visual Memory: [Brief Visuospatial Memory Test-revised (BVMT-R total score and delayed recall), TFC memory]; Executive Functions: [Modified Wisconsin Card Sorting Test (M-WCST total categories, perseverative errors and total errors), TMT Part B]; Verbal fluency: letters F, A, S, and P.

Fig. 4

Predicted effects of age, education, CAG repeats, motor status, executive functions and verbal fluency in cognition by groups. Pre-manifest patients. Early manifest HD patients. Manifest HD patients. The figure illustrates the percentage of variance explained by age education and clinical data in each model separately by pre-manifest HD, early manifest HD, and manifest HD group. Note: Motor status was assessed with the Unified Huntington’s Disease Rating Scale (UHDRS): General cognition was assessed with the Montreal Cognitive Assessment (MoCA). Visual attention [TMT (Trail Making Test) part A, Stroop Word, Stroop Color, Stroop Word-Color]; Visual processing speed/visual perception [Salthouse Perceptual Comparison Test (SPCT), Symbol Digit Modalities Test (SDMT)]; Visuospatial abilities: [Grooved Pegboard test (GPT), Visual perception with Visual Object and Space Perception Battery (VOSP cubes and dot-counting), Taylor Complex Figure (TFC copy), Benton Judgment of Line Orientation (BJLO)]; Visual Memory: [Brief Visuospatial Memory Test-revised (BVMT-R total score and delayed recall), TFC memory]; Executive Functions: [Modified Wisconsin Card Sorting Test (M-WCST total categories, perseverative errors and total errors), TMT Part B]; Verbal fluency: letters F, A, S, and P.

Fig. 5

ROC Curve of cognitive domains between groups. Note: This image displays ROC curves (Receiver Operating Characteristic) from three comparisons related to Huntington’s Disease (HD) [Healthy controls vs. Manifest HD patients (early manifest and manifest group), Pre-manifest HD vs. Manifest HD (early manifest and manifest group), and Healthy controls vs. Pre-manifest HD] and different cognitive domains: General cognition measured by MoCA total, Visual attention [TMT (Trail Making Test) part A, Stroop Word, Stroop Color, Stroop Word-Color]; Visual processing speed/visual perception [Salthouse Perceptual Comparison Test (SPCT), Symbol Digit Modalities Test (SDMT)]; Visuospatial abilities: [Grooved Pegboard test (GPT), Visual perception with Visual Object and Space Perception Battery (VOSP cubes and dot-counting), Taylor Complex Figure (TFC copy), Benton Judgment of Line Orientation (BJLO)]; Visual Memory: [Brief Visuospatial Memory Test-revised (BVMT-R total score and delayed recall), TFC memory]; Executive Functions: [Modified Wisconsin Card Sorting Test (M-WCST total categories, perseverative errors and total errors), TMT Part B]; Verbal fluency: letters F, A, S, and P.